Abstract
In non-diabetic adult patients, hypoglycaemia may be related to drugs, critical illness, cortisol or glucagon insufficiency, non-islet cell tumour, insulinoma, or it may be surreptitious. Nevertheless, some hypoglycaemic episodes remain unexplained, and inborn errors of metabolism (IEM) should be considered, particularly in cases of multisystemic involvement. In children, IEM are considered a differential diagnosis in cases of hypoglycaemia. In adulthood, IEM-related hypoglycaemia can persist in a previously diagnosed childhood disease. Hypoglycaemia may sometimes be a presenting sign of the IEM. Short stature, hepatomegaly, hypogonadism, dysmorphia or muscular symptoms are signs suggestive of IEM-related hypoglycaemia. In both adults and children, hypoglycaemia can be clinically classified according to its timing. Postprandial hypoglycaemia can be an indicator of either endogenous hyperinsulinism linked to non-insulinoma pancreatogenic hypoglycaemia syndrome (NIPHS, unknown incidence in adults) or very rarely, inherited fructose intolerance. Glucokinase-activating mutations (one family) are the only genetic disorder responsible for NIPH in adults that has been clearly identified so far. Exercise-induced hyperinsulinism is linked to an activating mutation of the monocarboxylate transporter 1 (one family). Fasting hypoglycaemia may be caused by IEM that were already diagnosed in childhood and persist into adulthood: glycogen storage disease (GSD) type I, III, 0, VI and IX; glucose transporter 2 deficiency; fatty acid oxidation; ketogenesis disorders; and gluconeogenesis disorders. Fasting hypoglycaemia in adulthood can also be a rare presenting sign of an IEM, especially in GSD type III, fatty acid oxidation [medium-chain acyl-CoA dehydrogenase (MCAD), ketogenesis disorders (3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) lyase deficiency, and gluconeogenesis disorders (fructose-1,6-biphosphatase deficiency)].
Highlights
Inborn errors of metabolism (IEM) are inherited diseases, usually recessive, which have recently become an important unrecognized part of adult medicine. They are usually classified into 3 main groups: 1) intoxication diseases; 2) diseases linked to energy deficiency
In a non-diabetic adult patient, hypoglycaemia may be related to drugs, critical illness, cortisol or glucagon insufficiency, non-islet cell tumour, insulinoma, or it may be surreptitious (Figure 1) [2]
Muscular manifestations associated with a high CPK, unexplained cardiomyopathy, an increase in some forms of acylcarnitine and a carnitine defect should lead to investigation for fatty acid oxidation disorders
Summary
Inborn errors of metabolism (IEM) are inherited diseases, usually recessive, which have recently become an important unrecognized part of adult medicine. Fasting hypoglycaemia may be caused by an IEM that was already diagnosed in childhood and persists into adulthood, and may sometimes even be a presenting sign of the disease These IEM include liver glycogen storage disease, fatty acid oxidation and ketogenesis defects, and gluconeogenesis disorders. If IEM-related fasting hypoglycaemia is suspected, the following minimal investigations should be performed: a abdominal ultrasound, EKG, echocardiography and laboratory measurements including acylcarnitine profile, total and free carnitin, urine organic acids, CPK, blood lactate levels, triglycerides, uric acid, liver enzymes. Muscular manifestations associated with a high CPK, unexplained cardiomyopathy, an increase in some forms of acylcarnitine and a carnitine defect should lead to investigation for fatty acid oxidation disorders In this case, fasting is not mandatory and could be even harmful because of the risk of cardiac arrhythmias, especially in MCAD and VLCAD. The orientation of the diagnosis will be based on the results of this fast (Figure 2)
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